Is angiogenesis a hallmark of prostate cancer?

Abstract

In vertebrate organogenesis, the blood vessels constitute the first organ system that arises and reaches a functional state (Persson and Buschmann, 2011). Angiogenesis, the development of new branching vessels from existing vasculature, is a complex process observed in fetal growth, wound healing and endometrial hyperplasia associated with the menstrual cycle (Carmeliet, 2003). Under these conditions, it is highly regulated: i.e., “turned on” for brief periods of time and then completely inhibited. However, many human diseases, including tumors, are driven by persistently upregulated angiogenesis (Carmeliet, 2003, 2005; Hanahan and Weinberg, 2011). In some non-malignant diseases, such as lobular capillary hemangioma or keloid formation, angiogenesis is self-limited; however, this is not true of tumor angiogenesis, which, once begun, continues indefinitely until the entire tumor is eradicated or the host dies. Without blood vessels, tumors cannot grow beyond a critical size. Angiogenesis is regulated by a balance of proand anti-angiogenic molecules (Hanahan and Weinberg, 2011), secreted from cancer cells, endothelial cells and stromal cells (Fukumura et al., 1998), the relative contributions of which are likely to change with tumor type and site, as well as with tumor growth, regression and relapse. It is also ascertained that angiogenic vessels have a disorganized and irregular structure, and that the blood flow is abnormal. This is in contrast to the organized, regular structure and normal blood flow seen in mature vessels. Angiogenesis can be depicted as a non-linear dynamic process that is discontinuous in space and time, but advances through qualitatively different states. The term state defines the configuration pattern of the process at any given moment, and a dynamic process can be represented as a set of different states and a number of transitions from one state to another over a certain time interval. The continuum of these states generates a complex ramified structure that irregularly fills the surrounding environment. The main feature of the newly generated vasculature is the structural diversity of the vessel sizes, shapes, and connecting patterns. This is mainly due to the heterogeneous distribution of angiogenic regulators, such as vascular-endothelial growth factor, basic fibroblastic growth factor and angiopoietin, leading to hypoxic and acidic tumoral regions (Karlou et al., 2010). Moreover, although it is commonly believed that the endothelial cells making-up tumor vessels are genetically stable, tumor vasculature seems to be much more unpredictable (Streubel et al., 2004). These conditions all reduce the effectiveness of treatments, modulate the production of proand antiangiogenic molecules, and select a subset of more aggressive cancer cells with higher metastatic potential. The significance of angiogenesis in prostate cancer (PC) still remains controversial (Russo et al., 2012). While there are currently no markers of the net angiogenic activity of PC that can help investigators to design specific anti-angiogenic treatment strategies, it is reasonable to assume that the quantification of various aspects of tumor vasculature may provide an indication of angiogenic activity. One oftenquantified parameter of PC vasculature is microvessel density (MVD), which is used to allow a histological assessment of tumor angiogenesis. The results of studies carried out over the last decade have suggested the value of using MVD as a prognostic index in PC, and it has also assumed that MVD may reveal the degree of angiogenic activity in PC. MVD has, however, a number of limitations. The conflicting MVD results in PC are likely due to the differences in study designs: variability in patient population size, tumor topography, approach to selection of representative tumor areas, choice of endothelial marker, and actual counting method. The selection of the tumor area for MVD assessment has been based on two different approaches: (1) analysis of a few microscopic “hot spots” containing the maximal vascular density, and (2) selection of random representative areas of the tumor. The first approach is the most applied due to its simplicity, although there is no agreement among investigators regarding optimal microscope magnification, the number of vascular hot spots, and cutoff values for low vs. high MVD. The second approach of MVD assessment within larger representative areas or whole tissue may be more objective but involves more tedious examination. Despite its importance as a prognostic indicator in untreated tumors, MVD has not been shown to be a valid measure to guide or evaluate anti-angiogenic treatment (Hlatky et al., 2002). MVD does not appear to be predictive of tumor response under anti-angiogenic treatment and therefore may not be useful for stratifying patients for clinical trials (Rubin et al., 1999; Eberhard et al., 2000; Hlatky et al., 2002; Preusser et al., 2006; Erbersdobler et al., 2010). Low MVD does not portend a poor response to anti-angiogenic therapy (Vartanian and